Hemodialysis has been already carried out as a maintenance therapy for the patients suffering from chronic renal insufficiency. Further, working examples of the therapy such as continuous hemofiltration, continuous hemodiafiltration or continuous hemodialysis are increasing in recent years as an acute blood purification therapy for the patients of a severely diseased state suffering from, for example, acute renal insufficiency and sepsis. As to a material of hollow fiber membrane used for such a therapy, there have been utilized a material derived from nature such as cellulose or cellulose derivatives and a synthetic polymer material such as polysulfone resin, poly(methyl methacrylate), polyacrylonitrile or ethylene-vinyl alcohol copolymer.
Hemodialysis is carried out for two to three times a week and, since it is a maintenance therapy throughout the life, although the module for the hemodialysis is important for its dialyzing property, the safety thereof is also quite important. In order to achieve the high performance of the hollow fiber membrane, the so-called water permeation heightening where the permeability of the membrane to water is enhanced is common but, as a result of making the water permeation high, there is a risk that the membrane strength lowers or particularly the pressure resistance and strength to the pressurization from the dialysate side lower whereby detachment and leakage are resulted. In addition, as a result of making the water permeation high, there are problems such as a risk where the dialysate invades into the body of a patient by a backfiltration during the dialysis and the lowering of the strength to the pressure particularly from the dialysate side as well as occurrence of the detachment of adhered part of the hollow fiber membrane and the generation of leakage.
On the basis of the recognition that the contamination of the dialysate and the lack of biocompatibility of the blood purification module are the factors for the onset of a long-term complication of the dialyzing patient with amyloidosis or the like, the Japanese Society for Dialysis Therapy proposed the standard for water quality of the dialysate and the standard for property evaluation of the blood purification modules. (See Non-Patent Document 1.)
The present applicant already filed a patent application for the membrane where the smoothness of the membrane is enhanced by subjecting to an appropriate elongation in a coagulation bath so as to give a membrane being excellent in safety and efficiency-retaining ability where the water permeating efficiency is 1 to 30 mL/(m2·hr·mmHg) (See Patent Document 1). In this technique, the inner structure of the membrane is made into a uniform fine structure and the surface smoothness is enhanced whereby elution of hydrophilic polymer is suppressed and efficiency-retaining rate during contacting the blood is enhanced. However, considerations in the high efficiency of the type II or more with low water permeability and also in the resistance to the pressure from the dialysate side are not sufficient.
Now, the functional classification of the dialyzer will be simply summarized as follows. (Clearance is the value calculated on the basis of 1.5 m2.)
[Classification of Hollow Fiber Type and Laminated Layer Type (Keel Type)]
Type I: Its ultrafiltration rate is not less than 3.0 ml/mmHg/hr while its urea clearance is not less than 125 ml/min and it does not correspond to II to V.
Type II: Its ultrafiltration rate is not less than 3.0 ml/mmHg/hr, its urea clearance is not less than 150 ml/min, and its β2MG clearance is not less than 10 ml/min and is less than 30 ml/min.
Type III: Its ultrafiltration rate is not less than 3.0 ml/mmHg/hr, its urea clearance is not less than 150 ml/min, and its β2MG clearance is not less than 30 ml/min and is less than 50 ml/min.
Type IV: Its ultrafiltration rate is not less than 3.0 ml/mmHg/hr, its urea clearance is not less than 150 ml/min, and its β2MG clearance is not less than 50 ml/min and is less than 70 ml/min.
Type V: Its ultrafiltration rate is not less than 3.0 ml/mmHg/hr, its urea clearance is not less than 150 ml/min, and its β2MG clearance is not less than 70 ml/min.
In the Patent Document 2, there is disclosed a hollow fiber type blood purification module containing hollow fiber membranes comprising hydrophobic polymer and hydrophilic polymer where elution of the hydrophilic polymer is not more than 20 mg per m2 and a retaining rate of the water permeability during perfusion using bovine blood is excellent. According to this document, it is mentioned that a non-coagulating inner liquid is used and the coagulation bath temperature is made low whereby coagulation of a spinning dope of polyether sulfone is made mild whereupon the membrane structure can be made uniform and smooth. It is also mentioned that the fine structure is made optimum by giving an appropriate elongation in a coagulation bath. However, the hollow fiber membrane mentioned in this document is such a thing where its coagulating speed is controlled so that elution of the hydrophilic polymer is suppressed and membrane structure is made smooth and, further, deformation of pores is suppressed so that the efficiency-retaining ability during contacting the blood is enhanced. Thus, although it is a low water-permeating and well usable blood purification module in which contamination from the dialysate during dialysis is suppressed, it is not in such a membrane structure having excellent removing property of the low-molecular protein.
On the other hand, the Patent Document 3 discloses a hollow fiber type blood purification module for medical use having a high water permeating ability used for the treatment of chronic renal insufficiency where safety and module assembling property are excellent. More specifically, it is mentioned that membrane thickness of polysulfone hollow fiber membrane is not more than 60 μm, breaking strength of a single fiber is not more than 50 g, yield strength is not more than 30 g, and crimps where wavelength is not less than 10 mm and amplitude is not less than 0.2 mm are given to the hollow fiber membrane; that the rate of the modified hollow fiber membrane consisting of all of flat fiber, abnormally shaped fiber and clogged fiber contained in the adhered terminal surface during assembling the hollow fiber membrane into a blood purification module is not more than 0.5% of the total numbers of the cross section of the hollow fiber membrane; and that the urea clearance measured by using a blood purification module having 1.5 m2 membrane area based on the inner diameter of the hollow fiber membrane is not less than 160 mL/min. However, the hollow fiber membrane mentioned in said document is intended to be a highly efficient blood purification module by making the water permeability high and, for enhancing the strength of the hollow fiber membrane, the structure is made asymmetric and, further, the membrane thickness is made large.
The Patent Document 4 discloses a hydrophilized selective permeating membrane comprising hydrophobic polymer and hydrophilic polymer wherein the membrane structure is made into a uniform fine structure so that elution can be suppressed even if the hydrophilic polymer is not subjected to a cross-linking treatment. There is mentioned that, according to this technique, permeability of low-molecular solutes (urea where the molecular weight is 60; inulin where the molecular weight is 5200) is high in spite of the fact the membrane has low water permeability and that the UV absorption thereof measured according to the standards for the approval of dialysis-type artificial kidney devices is 0.00. However, the invention mentioned in this publication relates to a hydrophilized selective permeable membrane of the conventional low water permeation type and, in this membrane, removal of low-molecular proteins such as β2MG (where the molecular weight is 11600) is difficult.
The Patent Document 5 discloses a hollow fiber membrane where high resistance to chemicals and physical strength are available and, even when a treatment with chemicals and a backwashing for the regenerating treatment are conducted, the hydrophilic polymer is not flown out from the membrane and the separating property is not deteriorated. According to the description of this document, the outcome is that, in case a spinning dope wherein the concentration (viscosity) of the polymers therein is made within a specific range is used, the entire membrane is made into a tight and uniform structure and the hydrophilic polymer is locked in that structure whereupon the above-mentioned action and effect are achieved. However, in the hollow fiber membrane mentioned in this document, its membrane thickness is made large so as to enhance the fiber strength for such a purpose that not the pressure resistance during dialysis but the resistance to chemical treatment and also to backwashing is to be enhanced.
The Patent Document 6 discloses a hollow fiber membrane having high water permeability and large pore size for the plasma separation where the membrane comprises a copolymer of ethylene vinyl alcohol. This hollow fiber membrane has the thickness of 15 to 17 μm and the breakage strength of 2.1 to 4.1 kg/cm2 (0.2 to 0.4 MPa) when a blood purification module is formed from this hollow fiber membrane and the blood outlet of the module is sealed under such a state that the module is dipped in water of 37° C., then pressure of air is gradually applied from the blood inlet and then the hollow fiber membrane is broken.